Multiomics and blood-based biomarkers of electroconvulsive therapy in severe and treatment-resistant depression: study protocol of the DetECT study.

Electroconvulsive therapy (ECT) is commonly used to treat treatment-resistant depression (TRD). However, our knowledge of the ECT-induced molecular mechanisms causing clinical improvement is limited. To address this issue, we developed the single-center, prospective observational DetECT study ("Multimodal Biomarkers of ECT in TRD"; registered 18/07/2022, www.clinicalTrials.gov , NCT05463562). Its objective is to identify molecular, psychological, socioeconomic, and clinical biomarkers of ECT response in TRD. We aim to recruit n = 134 patients in 3 years. Over the course of 12 biweekly ECT sessions (± 7 weeks), participant blood is collected before and 1 h after the first and seventh ECT and within 1 week after the twelfth session. In pilot subjects (first n = 10), additional blood draws are performed 3 and 6 h after the first ECT session to determine the optimal post-ECT blood draw interval. In blood samples, multiomic analyses are performed focusing on genotyping, epigenetics, RNA sequencing, neuron-derived exosomes, purines, and immunometabolics. To determine clinical response and side effects, participants are asked weekly to complete four standardized self-rating questionnaires on depressive and somatic symptoms. Additionally, clinician ratings are obtained three times (weeks 1, 4, and 7) within structured clinical interviews. Medical and sociodemographic data are extracted from patient records. The multimodal data collected are used to perform the conventional statistics as well as mixed linear modeling to identify clusters that link biobehavioural measures to ECT response. The DetECT study can provide important insight into the complex mechanisms of ECT in TRD and a step toward biologically informed and data-driven-based ECT biomarkers.

The biological classification of mental disorders (BeCOME) study: a protocol for an observational deep-phenotyping study for the identification of biological subtypes.

BACKGROUND: A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of the identified (neuro) biological dysfunctions are "transdiagnostic", meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications. METHODS: BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques. DISCUSSION: The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses. TRIAL REGISTRATION: Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).

Meta-analysis: Circulating vitamin D and ovarian cancer risk.

OBJECTIVE: To review and summarize evidence from longitudinal studies on the association between circulating 25 hydroxyvitamin D (25(OH)D) and the risk of ovarian cancer (OC). METHODS: Relevant prospective cohort studies and nested case-control studies were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardized manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, OC incidence according to circulating vitamin D status and the respective relative risks, and covariates adjusted for in the analysis. Due to the heterogeneity of studies in categorizing circulating vitamin D levels, all results were recalculated for an increase of circulating 25(OH)D by 20ng/ml. Summary relative risks (RRs) were calculated using meta-analysis methods. RESULTS: Overall, ten individual-level studies were included that reported on the association between circulating vitamin D levels and OC incidence. Meta-analysis of studies on OC incidence resulted in a summary RR (95% confidence interval, CI) of 0.83 (0.63-1.08) for an increase of 25(OH)D by 20ng/ml (P=0.160). No indication for heterogeneity and publication bias was found. CONCLUSIONS: A tentative inverse association of circulating 25(OH)D with OC incidence was found, which did not reach statistical significance but which requires clarification by additional studies due to potentially high clinical and public health impact.

Meta-analysis: Serum vitamin D and colorectal adenoma risk.

OBJECTIVE: To perform a systematic review and meta-analysis of human studies on the association between serum 25 hydroxyvitamin D (25(OH)D) and incident, sporadic colorectal adenoma (CRA) and CRA recurrence. METHODS: Relevant studies among humans were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. Due to the heterogeneity across studies in categorizing serum vitamin D levels, all results were recalculated for an increase of serum 25(OH)D by 20 ng/ml. Summary odds ratios (ORs) were calculated using meta-analysis methods. RESULTS: Overall, 10 original studies were included. Specific results for incident CRA according to serum 25(OH)D were reported in 8 studies, and for CRA recurrence in 2 studies, respectively. In meta-analyses, summary ORs (95% confidence intervals) regarding incident and recurrent CRA, and both outcomes combined were 0.82 (0.69-0.97), 0.87 (0.56-1.35), and 0.84 (0.72-0.97), respectively, for an increase of 25(OH)D by 20 ng/ml. No publication bias was found. CONCLUSION: Our results support suggestions that serum 25(OH)D levels are inversely associated with CRA risk.

Serum vitamin D and risk of secondary cardiovascular disease events in patients with stable coronary heart disease.

BACKGROUND: Recent longitudinal analyses suggested that low levels of serum 25-hydroxyvitamin D (25-OH-D) predict incident cardiovascular disease in initially healthy populations. Because the prognostic value of vitamin D for the occurrence of secondary cardiovascular events remains unclear, we examined the association of baseline 25-OH-D levels with prognosis in patients with stable coronary heart disease (CHD). METHODS: Serum 25-OH-D levels from 1,125 CHD patients of 2 German clinics undergoing a 3-week rehabilitation program after an acute cardiovascular event were measured, and participants were followed for up to 8 years. We used multivariate Cox regression analysis to model cardiovascular event incidence (fatal and nonfatal, including myocardial infarction, stroke, and death due to cardiovascular diseases) and all-cause mortality according to 25-OH-D quartiles, categories based on cut points of 15 and 30 ng/mL, or continuous vitamin D concentrations. RESULTS: During follow-up, 148 cardiovascular events and 121 deaths were recorded. Elevation of risk for the lowest quartile or category in comparison to the highest category was weak and nonsignificant for both incidence (hazard ratio [HR](quartile1) = 1.15 [0.72-1.84], HR(<15 ng/mL) = 1.17 [0.61-2.23]) and mortality (HR(quartile1) = 1.29 [0.77-2.14], HR(<15 ng/mL) = 1.87 [0.91-3.82]) in unadjusted Cox regression analysis and disappeared entirely after adjustment for potential confounders (cardiovascular events: HR(quartile1) = 0.84 [0.47-1.50], HR(<15 ng/mL) = 0.90 [0.41-1.96]; mortality: HR(quartile1) = 0.63 [0.33-1.21], HR(<15 ng/mL) = 0.93 [0.39-2.21]). Models treating vitamin D as a continuous variable likewise suggested no significant associations. CONCLUSIONS: Unlike previous population-based studies, our analysis in high-risk patients with stable CHD does not support a prognostic value of baseline-25-OH-D levels for secondary cardiovascular event incidence or all-cause mortality.

Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies.

BACKGROUND: Low serum 25-hydroxyvitamin D (25-OH-D) has recently been linked to cardiovascular diseases. This review summarizes evidence from prospective studies evaluating the prognostic value of 25-OH-D for cardiovascular disease incidence and mortality. METHOD: A systematic literature search in EMBASE and Pubmed-Medline databases was performed until November 2009. Prospective studies published in English were selected reporting estimates for the association of 25-OH-D with primary or secondary cardiovascular event incidence or mortality in the general population or subjects with prevalent cardiovascular disease. Pooled risk estimators were derived by meta-analysis using a random effects model approach. RESULTS: Four incidence and five independent mortality studies were included. Two incidence and three mortality studies reported a two- to five-fold risk increase for both outcomes in subjects with lower 25-OH-D, while the others did not detect a significant association. Meta-analysis supported the existence of an inverse association. CONCLUSION: Data from prospective investigations suggest an inverse association between 25-OH-D and cardiovascular risk. However, given the heterogeneity and small number of longitudinal studies, more research is needed to corroborate a potential prognostic value of 25-OH-D for cardiovascular disease incidence and mortality.

Prognostic value, clinical effectiveness, and cost-effectiveness of high-sensitivity C-reactive protein as a marker for major cardiac events in asymptomatic individuals: a health technology assessment report.

OBJECTIVES: The aim of this study was to compare the predictive value, clinical effectiveness, and cost-effectiveness of high-sensitivity C-reactive protein (hs-CRP)-screening in addition to traditional risk factor screening in apparently healthy persons as a means of preventing coronary artery disease. METHODS AND RESULTS: The systematic review was performed according to internationally recognized methods. Seven studies on risk prediction, one clinical decision-analytic modeling study, and three decision-analytic cost-effectiveness studies were included. The adjusted relative risk of high hs-CRP-level ranged from 0.7 to 2.47 (p < .05 in four of seven studies). Adding hs-CRP to the prediction models increased the areas under the curve by 0.00 to 0.027. Based on the clinical decision analysis, both individuals with elevated hs-CRP-levels and those with hyperlipidemia have a similar gain in life expectancy following statin therapy. One high-quality economic modeling study suggests favorable incremental cost-effectiveness ratios for persons with elevated hs-CRP and higher risk. However, many model parameters were based on limited evidence. CONCLUSIONS: Adding hs-CRP to traditional risk factors improves risk prediction, but the clinical relevance and cost-effectiveness of this improvement remain unclear.

Calcium, phosphate and the risk of cardiovascular events and all-cause mortality in a population with stable coronary heart disease.

OBJECTIVE: High serum calcium and phosphate levels have been linked to cardiovascular diseases and all-cause mortality but evidence from longitudinal studies is scarce, especially among patients with pre-existing coronary heart disease. The association between baseline calcium and phosphate and prognosis was examined in a cohort study of patients with stable coronary heart disease. METHODS: Serum calcium and phosphate were measured in a cohort of initially 1206 patients undergoing a 3 week rehabilitation programme after an acute cardiovascular event and subsequently being followed-up for 8 years. Multivariate Cox regression was employed to assess the association of quartiles and continuous levels of calcium and phosphate with secondary cardiovascular events and all-cause mortality. RESULTS: No significant risk elevations were observed for secondary cardiovascular event incidence in models adjusted for a variety of potential confounders. High calcium levels, however, were strongly associated with mortality risk in adjusted models (HR(Q4vsQ1)=2.39 (1.22 to 4.66)). In additional multivariable analyses, the calcium/albumin ratio was predictive for all-cause mortality (HR(Q4vsQ1)=2.66 (1.35 to 5.22)) and marginally predictive for cardiovascular event incidence (HR(Q4vsQ1)=1.74 (1.00 to 3.05)). CONCLUSIONS: Calcium and the ratio of calcium with albumin, its major binding protein, were strongly associated with all-cause mortality among patients with coronary heart disease. The underlying mechanisms and the clinical implications of these findings deserve further study.

Prognostic usefulness of free fatty acids in patients with stable coronary heart disease.

Circulating nonesterified or free fatty acids (FFAs) may contribute to the development of cardiovascular pathology and correlate with ischemia in acute cardiovascular conditions. The aim of this study was to assess whether serum levels of FFAs are associated with long-term prognosis in subjects with stable coronary heart disease. This observational prospective cohort study included 1,206 participants in 3-weeks inpatient rehabilitation programs after acute myocardial infarction, coronary syndromes, or coronary intervention at 2 rehabilitation clinics in Germany (1999 to 2000). Eight-year prognosis (time to a secondary fatal or nonfatal cardiovascular disease event including myocardial infarction and stroke [n = 153] and time to death from any cause [n = 124]) was examined according to FFA quartiles and in spline regression. FFAs were correlated with established serum markers of cardiovascular risk and strongly related to secondary cardiovascular events and all-cause mortality in age- and gender-adjusted analysis. When additionally controlling for multiple established risk factors and risk markers, the hazard ratio in the fourth versus first quartile was 1.34 (95% confidence interval 0.79 to 2.24) for secondary cardiovascular events and 1.09 (95% confidence interval 0.62 to 1.91) for all-cause mortality. Dose-response modeling suggested that very high FFAs might predict an increased risk for mortality (hazard ratio 1.98, 95% confidence interval 0.98 to 4.02, for 95th percentile vs first quartile). In conclusion, FFAs are closely correlated with cardiovascular risk markers, and in particular, very high FFA might identify patients with stable coronary heart disease with worse prognoses.

Serum parathyroid hormone and risk of adverse outcomes in patients with stable coronary heart disease.

BACKGROUND AND OBJECTIVE: Recent longitudinal studies have suggested an association of high serum parathyroid hormone levels (PTH) with elevated cardiovascular risk in the general population. This study presents analyses of the prognostic value of baseline PTH for subsequent cardiovascular events and all-cause mortality in a high-risk population with stable coronary heart disease. METHODS: Based on measurements of PTH levels in 1133 patients recruited at two German rehabilitation clinics and followed over 8 years, multivariate Cox regression analysis was performed to estimate the risk of secondary cardiovascular events (including myocardial infarction, stroke and death due to cardiovascular diseases) and all-cause-mortality according to PTH quartiles (Q1-Q4) and continuous PTH concentrations. RESULTS: During follow-up, 153 cardiovascular events and 124 deaths occurred. Age and sex-adjusted Cox regression analysis yielded statistically significant positive associations of PTH with both cardiovascular event incidence and all-cause mortality (HR (95% CI) per SD increase of PTH: 1.35 (1.21-1.51) and 1.25 (1.11-1.42), respectively). Associations remained essentially unchanged after additional adjustment for multiple cardiovascular risk factors. More detailed dose-response analyses showed strong risk elevation for above-normal levels of PTH (> 95th percentile), with essentially no association at lower levels. CONCLUSION: The results of this first detailed study in a cohort of patients with stable coronary heart disease suggest an independent predictive value of above-normal PTH for the prognosis in patients with stable coronary heart disease.

Meta-analysis: serum vitamin D and breast cancer risk.

We reviewed and summarised observational epidemiological studies regarding the association between serum vitamin D (measured as 25(OH)D levels) and the risk of breast cancer (BC). Relevant studies published until September 2009 were identified by systematically electronic searching Ovid Medline, EMBASE and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardised manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, BC incidence/BC mortality according to serum 25-hydroxyvitamin D (25(OH)D) and the respective ratios, and covariates adjusted for in the analysis. All existing observational epidemiological studies that reported at least one serum 25(OH)D level in subjects in any time period before or after a diagnosis of breast cancer were included in our review. Individual and summary risk ratios (RRs) for an increase of serum 25(OH)D by 20ng/ml were calculated using meta-analysis methods. Only 25(OH)D was considered. Overall, 10 articles were included. Specific results for BC incidence were reported in nine articles and for BC mortality in one article. In meta-analyses, summary RRs (95% confidence interval (CI)) for an increase of 25(OH)D by 20ng/ml were 0.59 (0.48-0.73), 0.92 (0.82-1.04) and 0.73 (0.60-0.88) with P values of <0.001, 0.164 and 0.001 for case-control studies, nested case-control studies and both study designs combined, respectively. No indication for publication bias was found, but there was large heterogeneity between studies. In conclusion, while case-control studies with measurement of 25(OH)D after diagnosis suggest an inverse association, a statistically significant inverse association remained unconfirmed in prospective studies with measurement of 25(OH)D years before diagnosis. Further studies are needed to clarify the potential role and the relevant exposure time regarding vitamin D and breast cancer risk.

Prognostic value, clinical effectiveness and cost-effectiveness of high sensitivity C-reactive protein as a marker in primary prevention of major cardiac events.

BACKGROUND: In a substantial portion of patients (= 25%) with coronary heart disease (CHD), a myocardial infarction or sudden cardiac death without prior symptoms is the first manifestation of disease. The use of new risk predictors for CHD such as the high-sensitivity C-reactive Protein (hs-CRP) in addition to established risk factors could improve prediction of CHD. As a consequence of the altered risk assessment, modified preventive actions could reduce the number of cardiac death and non-fatal myocardial infarction. RESEARCH QUESTION: Does the additional information gained through the measurement of hs-CRP in asymptomatic patients lead to a clinically relevant improvement in risk prediction as compared to risk prediction based on traditional risk factors and is this cost-effective? METHODS: A literature search of the electronic databases of the German Institute of Medical Documentation and Information (DIMDI) was conducted. Selection, data extraction, assessment of the study-quality and synthesis of information was conducted according to the methods of evidence-based medicine. RESULTS: Eight publications about predictive value, one publication on the clinical efficacy and three health-economic evaluations were included. In the seven study populations of the prediction studies, elevated CRP-levels were almost always associated with a higher risk of cardiovascular events and non-fatal myocardial infarctions or cardiac death and severe cardiovascular events. The effect estimates (odds ratio (OR), relative risk (RR), hazard ratio (HR)), once adjusted for traditional risk factors, demonstrated a moderate, independent association between hs-CRP and cardiac and cardiovascular events that fell in the range of 0.7 to 2.47. In six of the seven studies, a moderate increase in the area under the curve (AUC) could be detected by adding hs-CRP as a predictor to regression models in addition to established risk factors though in three cases this was not statistically significant. The difference [in the AUC] between the models with and without hs-CRP fell between 0.00 and 0.023 with a median of 0.003. A decision-analytic modeling study reported a gain in life-expectancy for those using statin therapy for populations with elevated hs-CRP levels and normal lipid levels as compared to statin therapy for those with elevated lipid levels (approximately 6.6 months gain in life-expectancy for 58 year olds). Two decision-analytic models (three publications) on cost-effectiveness reported incremental cost-effectiveness ratios between Euro 8,700 and 50,000 per life year gained for the German context and between 52,000 and 708,000 for the US context. The empirical input data for the model is highly uncertain. CONCLUSION: No sufficient evidence is available to support the notion that hs-CRP-values should be measured during the global risk assessment for CAD or cardiovascular disease in addition to the traditional risk factors. The additional measurement of the hs-CRP-level increases the incremental predictive value of the risk prediction. It has not yet been clarified whether this increase is clinically relevant resulting in reduction of cardiovascular morbidity and mortality. For people with medium cardiovascular risk (5 to 20% in ten years) additional measurement of hs-CRP seems most likely to be clinical relevant to support the decision as to whether or not additional statin therapy should be initiated for primary prevention. Statin therapy can reduce the occurrence of cardiovascular events for asymptomatic individuals with normal lipid and elevated hs-CRP levels. However, this is not enough to provide evidence for a clinical benefit of hs-CRP-screening. The cost-effectiveness of general hs-CRP-screening as well as screening among only those with normal lipid levels remains unknown at present.

[Prognostic value and clinical effectiveness of high sensitivity C-reactive protein as a marker in primary prevention of major cardiac events]. / Prognostische Wertigkeit und klinische Effektivität des hochsensitiven C-reaktiven Proteins als Marker in der Primärprävention der koronaren Herzkrankheit.

OBJECTIVE: To compare the predictive value and the clinical effectiveness of additional high sensitivity C-reactive protein (hs-CRP) screening as opposed to traditional risk factor screening alone as a strategy of primary prevention of coronary artery disease (CAD). METHODS: Following a comprehensive search of 26 electronic databases by DAHTA DIMDI, a systematic review was performed in accordance with international standards of evidence based medicine. Eight publications on risk prediction and one study addressing clinical decision-analytic modelling were included in the assessment. RESULTS: The adjusted relative risk of a high hs-CRP level (> 3 mg/L) for myocardial infarction, cardiac related death, and cardiovascular events ranged from 0.7 to 2.47 (p < 0.05 in 4 of 7 studies). The area under the receiver operating characteristic curve (AUC) increased by 0.00 to 0.027 when hs-CRP was added to the prediction models (4 of 7 studies statistically significant with p < 0.05). Based on a published decision-analytic model examining hs-CRP screening, the gain in life expectancy due to statin therapy in individuals with elevated hs-CRP was similar when compared to patients with hyperlipidaemia. Nonetheless, evidence on many model parameters was limited. CONCLUSION: Screening with hs-CRP in addition to traditional risk factors improves risk prediction. However, the incremental effect is moderate and the clinical relevance remains unclear.